The endothelium plays a pivotal role in maintaining vasodilation and acting as a permeability barrier. Impaired coronary endothelial function likely contributes to plaque progression and instability and predicts cardiovascular events. Systemic endothelium-dependent vasoreactivity is commonly measured in peripheral arteries like the brachial. Although brachial reactivity predicts cardiovascular event rates in population studies, coronary endothelial dysfunction is likely more closely linked to coronary atherosclerosis and cardiac events. Unfortunately, there is currently no non-invasive means for assessing endothelial function of the coronary arteries. We propose to develop, integrate, and test new non-invasive procedures for the evaluation of regional coronary artery endothelial function using high-field (3T) magnetic resonance imaging (MRI) to investigate the premise that local coronary endothelial function affects the progression of coronary atheroslcerosis, a regionally heterogeneous process. MRI offers high soft-tissue contrast images that can be used to measure arterial dimensions and blood flow. In addition, recent studies indicate that abnormal endothelial permeability can be detected as vessel wall enhancement in atherosclerotic regions with MRI. The PI has extensive experience in developing coronary MRI techniques and proposes here new procedures that include motion-suppressed high-resolution coronary lumen, flow, and vessel wall imaging, together with imaging of coronary artery endothelial permeability using contrast agents. The Specific Aims include defining endothelium-dependent and -independent coronary vasoreactivity in low- and high-risk populations. In patients with coronary artery disease, we propose to establish the spatial and temporal range of coronary endothelial permeability as assessed by delayed hyperenhancement of the normal and abnormal coronary artery vessel wall. Finally, we will test the hypothesis that coronary arterial endothelial dysfunction in a given coronary arterial segment relates to the subsequent development and progression of atherosclerotic disease in that segment. By the end of this grant period, we will have developed and optimized MRI methods for the truly non-invasive assessment of regional coronary artery endothelial function for the first time. The ability to non-invasively measure regional coronary vasoreactivity offers a greater fundamental understanding of the progression of atherosclerosis and may also lead to a true clinical paradigm shift. [unreadable] [unreadable] [unreadable]